Clinical profile of vigabatrin as monotherapy for treatment of infantile spasms

Jason T Lerner1, Noriko Salamon2, Raman Sankar1,31Departments of Pediatrics, 2Radiological Sciences, 3Neurology, David Geffen School of Medicine, University of California Los Angeles and Mattel Children’s Hospital at UCLA, Los Angeles, CA, USAAbstract: Vigabatrin, the first therapeutic agent to be approved by the Food and Drug Administration for the treatment of infantile spasms, as well as for adjunctive use in the treatment of refractory complex partial epilepsy, represents an important advance for patients with difficult-to-manage epilepsy. This review summarizes the complex history, chemistry, and pharmacology, as well as the clinical data leading to the approval of vigabatrin for infantile spasms in the US. The long path to its approval reflects the visual system and white matter toxicity concerns with this agent. This review provides a brief description of these concerns, and the regulatory safety monitoring and mitigation systems that have been put in place to enhance benefit over risk.Keywords: vigabatrin, infantile spasms, monotherap

A Role for the Intestinal Microbiota and Virome in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)?

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a heterogeneous disorder of significant societal impact that is proposed to involve both host and environmentally derived aetiologies that may be autoimmune in nature. Immune-related symptoms of at least moderate severity persisting for prolonged periods of time are common in ME/CFS patients and B cell depletion therapy is of significant therapeutic benefit. The origin of these symptoms and whether it is infectious or inflammatory in nature is not clear, with seeking evidence of acute or chronic virus infections contributing to the induction of autoimmune processes in ME/CFS being an area of recent interest. This article provides a comprehensive review of the current evidence supporting an infectious aetiology for ME/CFS leading us to propose the novel concept that the intestinal microbiota and in particular members of the virome are a source of the “infectious” trigger of the disease. Such an approach has the potential to identify disease biomarkers and influence therapeutics, providing much-needed approaches in preventing and managing a disease desperately in need of confronting

Norepinephrine and Corticosterone in the neoCLOM Animal Model of Obsessive Compulsive Disorder: Effects of Treatment and Sex

This study examined a novel animal model of OCD, the neoCLOM model, in which rats are treated twice daily from postnatal Days 9-16 with 15 mg/kg of the serotonin-norepinephrine uptake inhibitor clomipramine. Results showed there was an effect of neonatal TREATMENT on levels of norepinephrine (NE) measured from micropunches of post-mortem brain tissue using High Performance Liquid Chromatography. Compared to control males, neoCLOM males had higher levels of NE in the amygdala and the lateral thalamus. Compared to control females, neoCLOM females had higher levels of NE in the motor cortex, orbitofrontal cortex, and the hypothalamus. There was also an effect of SEX. Versus control males, control females had higher levels of NE in the lateral thalamus, ventral striatum, and anterior cingulate cortex. Conversely, levels of NE in the hypothalamus were lower in the control females versus males. Compared to neoCLOM males, neoCLOM females had higher levels of NE in the prefrontal cortex and the motor cortex. SEX (but not treatment) had a significant effect on corticosterone levels (rat analog of cortisol) in post-mortem trunk blood. The current finding that the elevation of NE evidenced in OCD was mirrored by increased levels of NE in brain structures of the neoCLOM rats adds support for the validity of this new animal model.https://orb.binghamton.edu/research_days_posters_spring2020/1075/thumbnail.jp

Pathogenic Cav3.2 channel mutation in a child with primary generalized epilepsy.

Two paternally-inherited missense variants in CACNA1H were identified and characterized in a 6-year-old child with generalized epilepsy. Febrile and unprovoked seizures were present in this child. Both variants were expressed in cis or isolation using human recombinant Cav3.2 calcium channels in tsA-201 cells. Whole-cell patch-clamp recordings indicated that one variant (c.3844C > T; p.R1282W) caused a significant increase in current density consistent with a pathogenic gain-of-function phenotype; while the other cis-related variant (c.5294C > T; p.A1765V) had a benign profile

Data-to-music API: Real-time data-agnostic sonification with musical structure models

Presented at the 21st International Conference on Auditory Display (ICAD2015), July 6-10, 2015, Graz, Styria, Austria.In sonification methodologies that aim to represent the underlying data accurately, musical or artistic approaches are often dismissed as being not transparent, likely to distort the data, not generalizable, or not reusable for different data types. Scientific applications for sonification have been, therefore, hesitant to use approaches guided by artistic aesthetics and musical expressivity. All sonifications, however, may have musical effects on listeners, as our trained ears with daily exposure to music tend to naturally distinguish musical and non-musical sound relationships, such as harmony, rhythmic stability, or timbral balance. This study proposes to take advantage of the musical effects of sonification in a systematic manner. Data may be mapped to high-level musical parameters rather than to one-to-one low-level audio parameters. An approach to create models that encapsulate modulatable musical structures is proposed in the context of the new DataTo- Music JavaScript API. The API provides an environment for rapid development of data-agnostic sonification applications in a web browser, with a model-based modular musical structure system. The proposed model system is compared to existing sonification frameworks as well as music theory and composition models. Also, issues regarding the distortion of original data, transparency, and reusability of musical models are discussed

Sources and characteristics of summertime organic aerosol in the Colorado Front Range: perspective from measurements and WRF-Chem modeling

Abstract. The evolution of organic aerosols (OAs) and their precursors in the boundary layer (BL) of the Colorado Front Range during the Front Range Air Pollution and Photochemistry Éxperiment (FRAPPÉ, July–August 2014) was analyzed by in situ measurements and chemical transport modeling. Measurements indicated significant production of secondary OA (SOA), with enhancement ratio of OA with respect to carbon monoxide (CO) reaching 0.085±0.003 µg m−3 ppbv−1. At background mixing ratios of CO, up to  ∼  1.8 µg m−3 background OA was observed, suggesting significant non-combustion contribution to OA in the Front Range. The mean concentration of OA in plumes with a high influence of oil and natural gas (O&G) emissions was  ∼  40 % higher than in urban-influenced plumes. Positive matrix factorization (PMF) confirmed a dominant contribution of secondary, oxygenated OA (OOA) in the boundary layer instead of fresh, hydrocarbon-like OA (HOA). Combinations of primary OA (POA) volatility assumptions, aging of semi-volatile species, and different emission estimates from the O&G sector were used in the Weather Research and Forecasting model coupled with Chemistry (WRF-Chem) simulation scenarios. The assumption of semi-volatile POA resulted in greater than a factor of 10 lower POA concentrations compared to PMF-resolved HOA. Including top-down modified O&G emissions resulted in substantially better agreements in modeled ethane, toluene, hydroxyl radical, and ozone compared to measurements in the high-O&G-influenced plumes. By including emissions from the O&G sector using the top-down approach, it was estimated that the O&G sector contributed to  <  5 % of total OA, but up to 38 % of anthropogenic SOA (aSOA) in the region. The best agreement between the measured and simulated median OA was achieved by limiting the extent of biogenic hydrocarbon aging and consequently biogenic SOA (bSOA) production. Despite a lower production of bSOA in this scenario, contribution of bSOA to total SOA remained high at 40–54 %. Future studies aiming at a better emissions characterization of POA and intermediate-volatility organic compounds (IVOCs) from the O&G sector are valuable

AR2, a novel automatic muscle artifact reduction software method for ictal EEG interpretation: Validation and comparison of performance with commercially available software.

Objective: To develop a novel software method (AR2) for reducing muscle contamination of ictal scalp electroencephalogram (EEG), and validate this method on the basis of its performance in comparison to a commercially available software method (AR1) to accurately depict seizure-onset location. Methods: A blinded investigation used 23 EEG recordings of seizures from 8 patients. Each recording was uninterpretable with digital filtering because of muscle artifact and processed using AR1 and AR2 and reviewed by 26 EEG specialists. EEG readers assessed seizure-onset time, lateralization, and region, and specified confidence for each determination. The two methods were validated on the basis of the number of readers able to render assignments, confidence, the intra-class correlation (ICC), and agreement with other clinical findings. Results: Among the 23 seizures, two-thirds of the readers were able to delineate seizure-onset time in 10 of 23 using AR1, and 15 of 23 using AR2 (